Clue to Nicotine Addiction Found

Caltech researchers have identified the site in the brain where nicotine exerts its most powerful effects, a finding that could lead to new ways to combat tobacco addiction.

Nicotine is generally considered one of the most addictive substances known, stronger than even cocaine and heroin, and the health effects of smoking are devastating. More than 4 million people worldwide die each year from diseases caused or exacerbated by smoking, but the majority of smokers are unable to stop.

The reason, according to Caltech biologist Henry A. Lester and his colleagues, is a receptor molecule in the brain called alpha4. The receptor is normally the target of a neurotransmitter called acetylcholine, which binds to it and causes a cell to release dopamine, which produces a pleasurable sensation.

Nicotine binds to the same receptor, also producing a pleasurable jolt. But the enzymes that destroy acetylcholine have no effect on nicotine, so it stays attached to the receptor much longer -- which may explain its great addiction potential.

Lester and his colleagues reported in this week’s Proceedings of the National Academy of Sciences that they identified alpha4’s key role by modifying its structure to make nicotine bind to it much more strongly.

They then exposed mice containing the altered receptors to very low levels of nicotine -- much too low to affect any other receptors in the brain -- and found that the animals still exhibited a very powerful response to the drug. That demonstrated that alpha4 was the key intermediary in nicotine addiction and suggested that developing drugs to block its activity might help wean people off smoking.